“Spinal CSF leaks can be incredibly debilitating, and in many cases we haven’t understood why they happen,” said Wouter Schievink, MD, co-senior author of the study and professor of Neurosurgery at Cedars-Sinai.

The brain and spinal cord are bathed in protective cerebrospinal fluid. A tear or hole in the membrane that surrounds the spinal cord can allow this fluid to leak out, leading to nausea, neck stiffness and severe headaches that worsen when standing. Current treatments for spinal CSF leaks focus on sealing the leak after it occurs. Patients are often treated with epidural blood patches, which can provide temporary relief, or may require specialized surgery to repair the tear when symptoms persist.

Spinal CSF leaks are associated with genetic connective tissue diseases that affect tissues supporting the body’s structure, but for many patients without a diagnosis of connective tissue disorder, the cause of the ruptured membrane is unknown.

“Because some patients with unexplained spinal CSF leak show subtle signs of connective tissue disease, even though they do not have a defined diagnosis, we sought to find a genetic cause,” Schievink said.

Investigators, including lead author of the study Cassie Parks, MD, PhD, and co-senior author Hal Dietz, MD, analyzed whole-exome sequencing from 42 patients with unexplained spinal CSF leak and compared the results with more than 3,800 individuals without the condition. They tested how the genetic variants they detected behave in human cells and laboratory mice.

The study found that about 1 in 5 patients with this type of spinal CSF leak had changes in the FBN2 gene, and that these changes appeared significantly more often in patients with CSF leak than in those without the condition.

Additional experiments showed that these genetic changes disrupt the way cells attach to the supportive tissue surrounding the spinal cord, potentially weakening this protective layer. In laboratory mice carrying the same mutations, the spinal lining was more prone to tearing and leaking.

Together, these findings suggest that defects in connective tissue caused by FBN2 variants may increase a person’s risk of developing spinal cerebrospinal fluid leaks.

“By identifying a genetic contributor, we now have the first understanding of cellular events that may be targetable for prevention or treatment of spontaneous CSF leaks,” said Dietz, professor of Genetic Medicine at the Johns Hopkins University School of Medicine.

“Potential future treatments can include medications that strengthen connective tissue or target the biological pathways affected by the FBN2 gene,” Schievink added.

Additional authors include Mukti Singh, Elizabeth Wohler, Renan Martin, Silke Peeters, Emily Juzwiak, Xinyi Sun, Bart Loeys, Nara Sobreira and Claire Baldock.

Funding: This work was supported by the Howard Hughes Medical Institute, the Marfan Foundation, the Pease/Scheeler Fund and the Biotechnology and Biological Sciences Research Council.

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Every minute counts when someone has a stroke, which occurs when blood flow to the brain is blocked. Without rapid treatment, brain cells begin dying within minutes, often leaving patients with permanent speech, movement or memory disabilities.

“Stroke is one of the most time-sensitive emergencies in medicine,” said Nestor Gonzalez, MD, director of the Neurovascular Laboratory in the Department of Neurosurgery at Cedars-Sinai. “The faster we restore blood flow to the brain, the more brain function we can preserve.”

Gonzalez’s advice is echoed in the American Heart Association and American Stroke Association’s new 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke. In the first update since 2019, the guidelines recommend more reliance on imaging, catheter-based procedures and emergency first responders. The guidelines also introduce the first national guidance for treating stroke in children.

Gonzalez, co-vice chair of the American Stroke Association group that developed the guideline, sat down with the Cedars-Sinai Newsroom to discuss the updates and leading-edge stroke research.

What are the most important changes in the updated guideline for acute ischemic stroke, in which a clot blocks blood flow to part of the brain?

Stroke treatment has advanced significantly over the past few decades, particularly with the development of clot-dissolving drugs and catheter-based procedures that can remove blockages in the brain. Since the previous stroke guidelines were published in 2019, new clinical trials have expanded our understanding of which patients can benefit from these treatments.

Previous guidelines recommended endovascular [minimally invasive] clot-removal procedures within six hours of stroke onset, with only a small group of selected patients eligible for treatment up to 24 hours after onset. The updated guideline broadens those criteria, allowing more patients to be considered for treatment in the 24-hour time frame.

The guidelines also expand treatment options for patients with large-core strokes—cases in which a significant area of the brain is affected. In the past, physicians were often hesitant to treat these patients because the potential benefit was uncertain. However, several recent studies have shown that intervention can still reduce disability in some cases.

The guidelines also expand eligibility for endovascular clot-removal procedures to include patients with preexisting disabilities, reflecting evidence that treatment may help them return to their baseline level of function.

You are a faculty member at Cedars-Sinai Guerin Children’s, and the updated recommendations include the first dedicated guidance for treating stroke in children. Why is that important?

Stroke can occur at any age, including in children. However, because it is rare, clinicians may not immediately consider stroke when a child presents with sudden neurological symptoms.

The updated guidelines provide clinicians with practical guidance for recognizing and managing stroke in children. Until now, there were no dedicated recommendations specifically addressing treatment in this population. The guidelines address early recognition of stroke symptoms, imaging strategies and circumstances in which treatments such as intravenous thrombolysis [clot-dissolving medication given through an IV] or endovascular thrombectomy [procedure removing clots from the brain] may be considered.

Over the past several years, specialized centers have begun applying some of the endovascular stroke treatments developed for adults to pediatric patients, and outcomes suggest that children can benefit from these interventions.

How will the updated guidelines change the treatment stroke patients receive in hospitals?

The guidelines emphasize improving the entire system of stroke care so patients can be evaluated and treated rapidly. That process begins with recognizing symptoms in emergency medical services, prompt evaluation and use of specialized treatment. They also synthesize a large body of research into recommendations that clinicians can apply in real-world practice.

The updated recommendations also highlight the importance of coordinated stroke systems that include rapid imaging, telemedicine support for smaller hospitals, and efficient patient transport to specialized stroke centers capable of performing advanced procedures, like Cedars-Sinai Medical Center.

For adult stroke patients, many of these systems are already in place. But for pediatric stroke, the impact may be even greater, as many hospitals are still developing formal systems for diagnosing and treating stroke in children.

What areas of stroke research are you most excited about right now?

Much of the recent progress in stroke care has focused on treating patients in the acute phase, when a clot suddenly blocks blood flow to the brain. But another challenge is helping patients whose brains receive chronically reduced blood flow, putting them at risk for repeated strokes. Two conditions that can cause this are Moyamoya disease, which often affects children and young adults, and intracranial atherosclerosis, which is more common in older adults.

In Moyamoya disease, the arteries at the base of the brain narrow or become blocked. To treat it, surgeons can perform bypass procedures that create new pathways to restore blood flow to the brain. My research has focused on improving these techniques and understanding how they benefit patients.

In adults with intracranial atherosclerosis, plaque buildup narrows, thickens or hardens the arteries in the brain. Medications help many patients, but in some cases, it is not enough. Working with the National Institutes of Health, we have been studying a surgical technique called indirect revascularization, or EDAS. Originally developed for children with Moyamoya disease, this approach is now being adapted for adults with severe vascular disease. Early clinical trials have shown encouraging results, and we are working to expand those studies to multiple centers to determine whether the technique can improve outcomes for patients who currently have limited treatment options.

Cedars-Sinai Health Sciences University is advancing groundbreaking research and educating future leaders in medicine, biomedical sciences and allied health sciences. Learn more about the university.

“We discovered that abnormal tau proteins accumulate in retinal ganglion cells, which are key nerve cells in the eye that send information to the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “We also identified a correlation between early accumulation of abnormal tau and the damage and death of retinal ganglion cells in people showing symptoms of mild cognitive impairment and Alzheimer’s disease.”

People with mild cognitive impairment and Alzheimer’s disease had 46%–57% fewer retinal ganglion cells than people with normal cognition, and their retinal ganglion cells were misshapen and prone to die. Harmful tau proteins were two to three times more common in the retinal ganglion cells of these people, and the amount of tau-related damage in the retina was linked to Alzheimer’s-related damage to the brain and a decline in cognitive function, Koronyo-Hamaoui said.

Additional Cedars-Sinai Authors: Miyah R. Davis, Edward Robinson, Yosef Koronyo, Altan Rentsendorj, Bhakta P. Gaire, Nazanin Mirzaei, Alexander V. Ljubimov, Keith L. Black, Dieu-Trang Fuchs

Additional Authors: Elena Salobrar-Garcia, Rakez Kayed, Alfredo A. Sadun, Lon S. Schneider, Debra Hawes

Funding: This work was supported by the National Institutes of Health (NIH)/the National Institute on Aging (NIA) through the following grants: R01 AG055865 and R01 AG056478 (M.K.H.), The Hertz Innovation Fund (M.K.H.), and the Gordon, Wilstein, and Saban Private Foundations (M.K.H.). Y.K., A.R., B.P.G., D.-T.F., M.K.H. are also supported, in part, by the NIH/NIA R01AG075998 grant. M.R.D. and E.R. are supported by The Ray Charles Foundation. E.S.G. is supported by José Castillejo grants for mobility stays abroad for young doctors 2023 (CAS22/00049, Ministerio de Ciencia, Investigación y Universidades) and Complutense del Amo Grants 2023, Complutense University of Madrid.

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“The retina, a layer of tissue at the back of the eye, is part of the central nervous system and is directly connected with the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai and senior author all three studies. “It has similar cell types and vascular structures to the brain, but is not shielded by bone, so it is more accessible to noninvasive imaging. Our latest research unearths new details about the eye-brain connection.”

Tau

Tau is a protein that helps stabilize the structure of nerve cells in the brain and the retina and is one of the key markers of Alzheimer’s disease. When tau disengages from nerve cells it can form tangles that interfere with cellular function and contribute to cognitive decline.

In a study published in the peer-reviewed journal Acta Neuropathologica, Koronyo-Hamaoui and fellow investigators compared retinal tissue from 45 patients diagnosed with Alzheimer’s-related cognitive impairment or dementia with tissue from 34 individuals with normal cognition or non-Alzheimer’s forms of dementia.

Investigators found that higher levels of abnormal tau in the retina corresponded to levels of tau in the brain, other brain changes related to Alzheimer’s disease, and cognitive decline.

Vessels and amyloid plaques

Clumps of a protein called beta-amyloid, also known as amyloid plaques, are another hallmark of Alzheimer’s disease.

In a study published in the peer-reviewed journal Acta Neuropathologica Communications, Koronyo-Hamaoui and co-investigators used leading-edge imaging and image-processing technology to compare amyloid plaques in the retinas of living patients who had early-stage cognitive impairment with those in individuals who had normal cognition.

Thirty-four patients underwent retinal and brain imaging, and cognitive testing. Analysis in 28 patients revealed two to three times as many plaques clustered near blood vessels in the retinas of patients with mild cognitive impairment or Alzheimer’s disease when compared with individuals with normal cognition. The numbers and position of the plaques correlated with cognitive decline and physical changes in the brain.

Diagnosis in development

Koronyo-Hamaoui’s team also published a review article in the peer-reviewed journal Progress in Retinal and Eye Research that detailed additional Alzheimer’s disease biomarkers that have been identified in the retina.

These include reduced blood flow, deposits of amyloid-beta proteins inside blood vessel walls, damage to the barrier that prevents harmful substances from entering retinal tissue, inflammation, and damage to nerve cells.

“Imaging technology now being developed will allow us to see these changes in patients in clinical settings,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai and co-author of these studies. “This technology, which is noninvasive and affordable, allows us to see changes in the cells and blood vessels in tremendous detail.”

Black and Koronyo-Hamaoui envision this technology as a tool to screen patients in primary care settings, with those who show features suggestive of Alzheimer’s disease referred for additional testing, such as a PET brain scan or cerebrospinal fluid or blood test. The technology could also assess disease progression and the effectiveness and safety of new treatments.

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This could lead to new applications for the therapy, allowing it to influence higher-level functions such as learning and memory.

“Deep brain stimulation has typically been used to overexcite or shut down all neurons in a target area,” said Costas Anastassiou, PhD, associate professor of Neurology, Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “We found that by varying the shape of the electrical pulse waves we apply, we can selectively influence specific neuron types while leaving others unaffected.”

In the study, investigators applied electrical fields to individual cells in tissue samples from the visual cortex and the hippocampal regions of the brains of patients and laboratory mice. The investigators recorded the activity of excitatory and inhibitory neurons, which act as the gas pedal and brakes, respectively, in brain circuits.

Results showed that different electrical wave frequencies influenced the timing of spikes, which are changes in electrical voltage that travel down neuron fibers and are transmitted to other neurons. Anastassiou called spikes “the coin of communication between neurons.”

“We found that electrical frequencies that influenced one cell type did not necessarily influence another, and vice versa,” Anastassiou said. “Surprisingly, the effects on each cell type were the same in both brain areas we examined, and in both species—though more pronounced in humans than in mice.”

Given that previous research has found that higher-level functions in the brain require coordination and communication between different cell types, the ability to manipulate this communication could be of great importance, Anastassiou said.

“This study offers new understanding of how to stimulate the human brain to promote or suppress specific activity patterns, and could pave the way for new directions in basic research and clinical applications,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “These results offer the possibility for electrical protocols that are more selective, more controlled, and allow for different parts of the brain neural network to be manipulated in different ways.”

Investigators are now working to determine the exact mechanisms required to produce various results in the brain, and to replicate their brain tissue experiments in living patients.

“This data supports the idea that electrical brain stimulation could be used in new ways that target specific groups of brain cells,” said Adam Mamelak, MD, director of the Functional Neurosurgery Program at Cedars-Sinai. “This gives us an exciting opportunity to imagine new uses for this therapy and the chance to address disorders involving learning and memory.” 

Other Cedars-Sinai authors involved in the study include Konstantinos Kozalakis, PhD.

Funding: This work was supported by National Institutes of Health grants R01 NS120300 and RO1 NS130126.

Conflict of interest: Anastassiou is listed as an inventor on a patent application related to this work.

Learn more on the Cedars-Sinai Blog: A Patient’s Journey With Deep Brain Stimulation

The Rutishauser Lab collaborates with several leading universities and medical centers, including the California Institute of Technology, Johns Hopkins University, the University of Toronto, Boston Children’s Hospital and the University of Colorado at Denver. A key aspect of this collaboration is open data-sharing. Cedars-Sinai is part of the National Institutes of Health BRAIN Initiative Research Opportunities in Humans Consortium, representatives of which recently penned an article for the peer-reviewed journal Neuron on the benefits of data-sharing.

“Dr. Rutishauser’s work advances our understanding of the workings of the human brain and also connects Cedars-Sinai with top medical institutions across the country and beyond,” said Jeffrey Golden, MD, vice dean of Research and Research Education at Cedars-Sinai. “Work of this caliber simply isn’t possible if institutions guard their discoveries and data, encumbering collaboration.”

Rutishauser, who holds the Board of Governors Chair in Neurosciences, sat down with the Cedars-Sinai Newsroom to discuss the role of data-sharing and scientific collaboration in his work and the broader scientific community.

What type of data does your lab’s research generate, and how has it advanced our understanding of the human brain?

Our data is acquired from patients with epilepsy who are undergoing depth-electrode monitoring, which means they have tiny electrodes surgically inserted into the brain to monitor seizure activity.

We use these recordings of the electrical pulses sent between individual neurons within the brain to study how the brain records and recalls memories, how we make decisions, and how these processes go wrong under certain conditions. For example, we have discovered how we monitor our own behavior for errors using this approach.

The same data, which is rare and difficult to acquire, can also be used to study many other aspects of the human brain, but this is only possible if the data is made accessible to other investigators inside and outside of Cedars-Sinai.

What is the current state of data-sharing in human neuroscience?

Funding agencies and journals require that research teams make their data available to others. However, they require sharing of only the exact data needed to reproduce a given study, often only on request.

This requirement is often viewed as a burden by investigators. But in our recent editorial, we point out the many benefits of investigators sharing all of their data freely and in a standardized format, so it is easily accessible. We found that when we, as the data producer, released data in this way, we discovered new collaborators who used our data to explore questions we had never thought about. Within our own lab, using a standardized data format also facilitated reuse of that data. And schools and universities have even used the data for teaching purposes.

Why is cross-institutional collaboration so important to the future of science?

Collaborating and sharing data is a way for us to broaden our impact. One of the inherent difficulties of the work I do is that the experiments are challenging to perform and the number of patients available is limited. To increase the amount of data available, we collaborate with research groups at other institutions. This allows us to perform large, well-powered studies and increases confidence in our findings by replicating findings at other institutions.

What challenges need to be overcome to increase data-sharing in neuroscience?

There are three challenges. First, the field has to agree on a standard data format. While there are formats that could fill this requirement, there’s no universal agreement on which should be the standard format. The use of a single standard data format in the field of neuroimaging, for example, shows the immense benefits of the practice. Second, we need data archives where very large files can be uploaded, stored and made available. Third, and perhaps most challenging, investigators must be willing to openly share their data.

What is your advice for investigators who want to share their data?

I strongly advise using a standardized data format. We chose to use the Neural Data Without Borders (NWB) format. Develop an expectation in your lab that when a project is finished, your team will export the data in that format, document it and publicly release it upon publication.

A recent study published in Frontiers in Immunology offers broader insight into the protein networks that allow immune cells to respond to harmful substances. This discovery could lead to treatments that leverage the body’s natural healing processes.

“This study demonstrates enormous potential for exploiting the natural immune process to better fight disease,” said Maya Koronyo-Hamaoui, PhD, a professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “White blood cells—which we studied here in the context of Alzheimer’s disease—are one of the first lines of defense against a variety of foreign and internal threats and are key for regulating tissue repair and maintenance.”

The study demonstrates the significance of osteopontin (OPN), a protein expressed by macrophages, a type of white blood cell that surrounds and destroys harmful organisms and clears cell debris and the buildup of abnormal proteins. Investigators, in collaboration with the Van Eyk Research Lab at Cedars-Sinai, concluded that OPN deficiency disrupts the balance of proteins in macrophages, eventually causing them to die.

“Macrophages clear toxic proteins, reduce inflammation, and help regenerate, rejuvenate, and encourage newly formed connections in the brain,” said Koronyo-Hamaoui.

The study builds on two previous studies from the Koronyo-Hamaoui Llab—published in Brain Behavior and Immunity and Brain—detailing the critical role played by bone-marrow derived macrophages and OPN expressed in macrophages in clearing Alzheimer’s disease-related amyloid-beta peptides and supporting central nervous system repair and regeneration.

“Our work supports further study into gene editing or immunotherapies that could have multifaceted impact,” said Altan Rentsendorj, PhD, a senior research associate in the Koronyo-Hamaoui Lab and first author of the study.

Investigators studied macrophages in laboratory mice. They compared normal cells, diseased cells treated with an FDA-approved multiple sclerosis treatment that caused them to overexpress OPN, and cells without the ability to produce OPN.

They found that diseased macrophages treated with the multiple sclerosis medication more effectively cleared amyloid-beta proteins and increased their anti-inflammatory activity. However, in cells without the ability to produce OPN, treatment with the multiple sclerosis medication did not restore normal protein expression.

Investigators also discovered that the presence of OPN is necessary to produce two other crucial anti-inflammatory molecules. Dysfunction of the first, ubiquitin C-terminal hydrolase L1, has been implicated in neurodegenerative diseases such as Alzheimer’s. The second, heme oxygenase 1, plays a critical role in preventing vascular inflammation.

“We were surprised to find that other neuroprotective proteins are dependent on OPN,” Rentsendorj said. “This work shows that OPN is critical for the machinery of rejuvenation in these innate immune cells.”

The Koronyo-Hamaoui Lab also recently published a review paper in Frontiers in Physiology synthesizing knowledge about angiotensin converting enzyme (ACE) and its role in Alzheimer’s disease. ACE, expressed by immune cells, degrades amyloid-beta and improves immune response.

The review outlines findings from 1975 onward, including numerous studies from the Koronyo-Hamaoui Lab in collaboration with the Bernstein Lab at Cedars-Sinai.

Significant among these are a 2020 paper published in Brain, which demonstrated that overexpression of ACE enhances the ability of white blood cells called monocytes to rid the body of toxic forms of amyloid-beta oligomers and fibrils, and a 2014 paper published in The Journal of Clinical Investigation. The review also notes that an analysis of human genome sequencing found people with a genetic variant that leads to lower expression of ACE in their blood had higher risk for Alzheimer's disease.

“This review builds a strong case for targeting monocytes and ACE in Alzheimer's disease,” said neurology fellow Ron Danziger, MD, first author of the review paper. “In extensive studies by the Koronyo-Hamaoui and Bernstein labs, we have consistently found an amazing effect of ACE on the characteristics of macrophages in the context of Alzheimer’s disease.”

Taken together, the new papers support the need for further research into therapies that might leverage immune function in blood or bone marrow cells to fight neurodegenerative disease.

“We need a much more effective treatment to address many aspects of Alzheimer’s disease,” said Keith L. Black, MD, chair of the Department of Neurosurgery, the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and co-author of both studies. “Genetically manipulating monocytes to enhance ACE or OPN, which would target more than plaque clearance, could be a very promising technique.”

Funding: The study appearing in Frontiers in Immunology was funded by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG056478, R01AG055865, AG056478-04S1 and R01AG075998) and the Tom Gordon, Haim Saban and Wilstein foundations.

The study appearing in Frontiers in Physiology was supported by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG055865, R01AG056478, R01AG075998 and R01AG042195); a BrightFocus Foundation Award; The Coins for Alzheimer’s Research Trust (CART) Fund; the Cedars-Sinai Jona Goldrich Center for Alzheimer’s and Memory Disorders; the Saban, Gordon, Marciano and Wilstein private foundations; and the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124).

Read more from the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer’s or Dementia